Processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates

ABSTRACT

Novel processes, and intermediates, for making alkylated arylpiperazine and alkylated arylpiperidine compounds of the general formulas (I) and (VII), respectively 
     
       
         
         
             
             
         
       
     
     wherein, R 1  and R 2  are individually selected from hydrogen, alkyl, substituted or alkyl; n=0, 1, or 2; Y=NR 3 R 4 , OR 5 , or SR 5 , where R 3  and R 4  are individually selected from acyl or sulfonyl, and where R 5  is aryl or heteroaryl, or heterocyclic; and Ar is an aryl, heteroaryl, or heterocyclic compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. Provisional Patent ApplicationNo. 62/012,701, filed Jun. 16, 2014, the disclosures of which areincorporated herein by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present disclosure provides processes for making alkylatedarylpiperazine and alkylated arylpiperidine compounds as well as novelintermediate compounds formed during those processes.

BACKGROUND OF THE INVENTION

The piperazines are a broad class of chemical compounds, many withimportant pharmacological properties, which contain a core piperazinefunctional group. Many currently notable pharmaceutical drugs contain apiperazine ring as part of their molecular structure. Examples include:antianginals (ranolazine, trimetazidine); antidepressants (amoxapine,befuraline, buspirone, flesinoxan, gepirone, ipsapirone, nefazodone,piberaline, tandospirone, trazodone, vilazodone, zalospirone);antihistamines (buclizine, meclozine, cinnarizine, cyclizine,hydroxyzine, cetirizine, levocetirizine, niaprazine); antipsychotics(fluphenazine, perphenazine, trifluoperazine, prochlorperazine,thiothixene, flupentixol, zuclopenthixol, amperozide, aripiprazole,lurasidone, clozapine, olanzapine, perospirone, ziprasidone);urologicals (sildenafil, vardenafil).

Piperidine is also widely used building block and chemical reagent inthe synthesis of organic compounds, including pharmaceuticals. Similarto piperazine, piperidine and its derivatives are ubiquitous buildingblocks in the synthesis of pharmaceuticals and fine chemicals. Forexample, the piperidine structure is found in the following classes ofpharmaceuticals: SSRI (selective serotonin reuptake inhibitors)(paroxetine); analeptics/nootropics (stimulants) (methylphenidate,ethylphenidate, pipradrol, desoxypipradrol); SERM (selective estrogenreceptor modulators) (raloxifene); vasodilators (minoxidil);neuroleptics (antipsychotics) (risperidone, thioridazine, haloperidol,droperidol, mesoridazine); opioids (pethidine, meperidine, loperamide).

Considering their prevalence in the formation of a variety of importantpharmaceutical compounds, there is a need for new and improved processesfor making both piperazine and piperidine compounds, includingintermediates and derivatives thereof, that minimizes the formation ofunwanted by-products and eliminates the need for additional purificationsteps where product is lost.

SUMMARY OF THE INVENTION

The present disclosure provides processes for making alkylatedarylpiperazine and alkylated arylpiperidine compounds, includingintermediates and derivatives thereof. More specifically, the presentinvention provides processes for making a variety of alkylatedarylpiperazine and alkylated arylpiperidine compounds of the generalformulas (I) and (VII), respectively,

wherein, R₁ and R₂ are individually selected from hydrogen,unsubstituted alkyl, and substituted alkyl, or R₁ and R₂ are connectedto form a 5 to 8 carbon cyclic ring; n is 0, 1, or 2; Y is NR₃R₄, OR₅,or SR₅, where R₃ and R₄ are individually selected from acyl or sulfonyl,wherein R₃ and R₄ may be connected to form a substituted orunsubstituted cyclic or bicyclic ring, and wherein R₅ is aryl orheteroaryl, or heterocyclic; and Ar is an aryl or heteroaryl group.

Novel intermediate compounds, made during the processes described andclaimed herein, are also disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

No drawings.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

All numerical designations, such as, weight, pH, temperature, time,concentration, and molecular weight, including ranges, areapproximations which are varied by 10%. It is to be understood, althoughnot always explicitly stated, that all numerical designations arepreceded by the term “about.” It also is to be understood, although notalways explicitly stated, that the reagents described herein are merelyexemplary and that equivalents of such are known in the art.

In reference to the present disclosure, the technical and scientificterms used in the descriptions herein will have the meanings commonlyunderstood by one of ordinary skill in the art, unless specificallydefined otherwise. Accordingly, the following terms are intended to havethe following meanings.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers.

For example, the compounds described herein can be in the form of anindividual enantiomer, diastereomer or geometric isomer, or can be inthe form of a mixture of stereoisomers, including racemic mixtures andmixtures enriched in one or more stereoisomer. Isomers can be isolatedfrom mixtures by methods known to those skilled in the art, includingchiral high pressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts; or preferred isomers can be prepared byasymmetric syntheses. The invention additionally encompasses compoundsdescribed herein as individual isomers substantially free of otherisomers, and alternatively, as mixtures of various isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋ ₅, and C₅₋₆ alkyl.

As used herein, the term “alkyl” means the monovalent linear or branchedsaturated hydrocarbon moiety, consisting solely of carbon and hydrogenatoms, having from one to twelve carbon atoms. “Lower alkyl” refers toan alkyl group of one to six carbon atoms, i.e., C₁-C₆ alkyl. Examplesof alkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl,dodecyl, and the like. “Branched alkyl” means, for example, isopropyl,isobutyl, and tert-butyl. Specifically included within the definition of“alkyl” are those aliphatic hydrocarbon chains that are optionallysubstituted.

As used herein, the term “alkylene” means a linear saturated divalenthydrocarbon radical of one to six carbon atoms or a branched saturateddivalent hydrocarbon radical of three to six carbon atoms, e.g.,methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene,butylene, pentylene, and the like.

As used herein, the term “aryl” refers to a radical of a monocyclic orpolycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having6-14 ring carbon atoms and zero heteroatoms provided in the aromaticring system (“C₆₋₁₄ aryl”). In some embodiments, an aryl group has sixring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, anaryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as1-naphthyl and 2-naphthyl). In some embodiments, an aryl group hasfourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” alsoincludes ring systems wherein the aryl ring, as defined above, is fusedwith one or more carbocyclic or heterocyclic groups wherein the radicalor point of attachment is on the aryl ring, and in such instances, thenumber of carbon atoms continue to designate the number of carbon atomsin the aryl ring system. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, and trinaphthalene. Particularly aryl groupsinclude phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

As used herein, the term “heteroaryl” refers to a radical of a 5-10membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having6 or 10 π electrons shared in a cyclic array) having ring carbon atomsand 1-4 ring heteroatoms provided in the aromatic ring system, whereineach heteroatom is independently selected from nitrogen, oxygen andsulfur (“5-10 membered heteroaryl”). In heteroaryl groups that containone or more nitrogen atoms, the point of attachment can be a carbon ornitrogen atom, as valency permits. Heteroaryl bicyclic ring systems caninclude one or more heteroatoms in one or both rings. “Heteroaryl”includes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more carbocyclic or heterocyclic groups wherein thepoint of attachment is on the heteroaryl ring, and in such instances,the number of ring members continue to designate the number of ringmembers in the heteroaryl ring system. “Heteroaryl” also includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more aryl groups wherein the point of attachment is either on thearyl or heteroaryl ring, and in such instances, the number of ringmembers designates the number of ring members in the fused(arylheteroaryl) ring system. Bicyclic heteroaryl groups wherein onering does not contain a heteroatom (e.g., indolyl, quinolinyl,carbazolyl, and the like) the point of attachment can be on either ring,i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

As used herein, the term “heterocyclic” refers to a radical of a 3 to 10membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclic”). In heterocyclic groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclic group can either be monocyclic(“monocyclic heterocyclic”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclic”), and can besaturated or can be partially unsaturated. Heterocyclic bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclic” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclic groups whereinthe point of attachment is either on the carbocyclic or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclic is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclic”) or substituted (a“substituted heterocyclic”) with one or more substituents. In certainembodiments, the heterocyclic group is unsubstituted 3-10 memberedheterocyclic. In certain embodiments, the heterocyclic group issubstituted 3-10 membered heterocyclic.

In some embodiments, a heterocyclic group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocylic”). In some embodiments, a heterocyclic group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclic”). In someembodiments, a heterocyclic group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclic”). In some embodiments, the 5-6 memberedheterocyclic has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclic has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclic has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclic groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclic groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclic groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclic groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclic groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclic groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclic groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8membered heterocyclic groups containing one heteroatom include, withoutlimitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-memberedheterocyclic groups fused to a C₆ aryl ring (also referred to herein asa 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclic groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

As used herein, the term “acyl” refers to a radical —C(O)R^(a), whereR^(a) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclic, substituted or unsubstituted heterocyclic,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative acyl groups include, butare not limited to, formyl (—CHO), acetyl (—C(═O)CH₃),cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph),benzylcarbonyl (—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀aryl), —C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclic), wherein tis an integer from 0 to 4.

As used herein, the term “alkoxy” refers to the group —OR^(b) whereR^(b) is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclic, substituted or unsubstituted heterocyclic,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e.,with between 1 and 6 carbon atoms. Further particular alkoxy groups havebetween 1 and 4 carbon atoms.

As used herein, the term “halo” or “halogen” refers to fluoro (F),chloro (Cl), bromo (Br), and iodo (I).

Alkyl, heterocyclic, aryl, and heteroaryl groups, as defined herein, areoptionally substituted (e.g., “substituted” or “unsubstituted” alkyl,“substituted” or “unsubstituted” heterocyclic, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, any of the substituentsdescribed herein that results in the formation of a stable compound. Thepresent invention contemplates any and all such combinations in order toarrive at a stable compound. For purposes of this invention, heteroatomssuch as nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Optional substituents for alkyl, alkenyl, aryl, heteroaryl, orheterocycle groups are well known to those skilled in the art. Thesesubstituents include alkyl, alkoxy, aryloxy, hydroxy, acetyl, cyano,nitro, glyceryl, and carbohydrate, or two substituents taken togethermay be linked as an -alkylene-group to form a ring.

As used herein, the term “leaving group” or “LG” means the group withthe meaning conventionally associated with it in synthetic organicchemistry, i.e., an atom or group displaceable under substitutionreaction conditions. Examples of leaving groups include, but are notlimited to, halogen, alkane- or arylenesulfonyloxy, such asmethanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy,tosyloxy, mesylate, and thienyloxy, dihalophosphinoyloxy, optionallysubstituted benzyloxy, isopropyloxy, acyloxy, and the like.

Preferred Embodiments of the Process of the Invention

The present invention provides processes for making arylpiperazine andarylpiperidine compounds, including intermediates and derivativesthereof. More specifically, the present invention provides processes ormethods for making a variety of alkylated arylpiperazine and alkylatedarylpiperidine compounds of the general formulas (I) and (VII),respectively.

wherein, R₁ and R₂ are individually selected from hydrogen,unsubstituted alkyl, and substituted alkyl, or R₁ and R₂ are connectedto form a 5 to 8 carbon cyclic ring; n is 0, 1, or 2; Y is NR₃R₄, OR₅,or SR₅, where R₃ and R₄ are individually selected from acyl or sulfonyl,wherein R₃ and R₄ may be connected to form a substituted orunsubstituted cyclic or bicyclic ring, and wherein R₅ is aryl orheteroaryl, or heterocyclic; and Ar is an aryl or heteroaryl group.

Arylpiperazine compounds of formula (I) include, for example,lurasidone, tiospirone, revospirone, perospirone, brexipirazole,aripiprazole, buspirone, gepirone, ipsapirone, eptapirone, umespirone,tandospirone, and zalospirone.

Arylpiperidine compounds of formula (VII) include, for example,iloperidone and abaperidone.

The processes for making the alkylated arylpiperazine and alkylatedarylpiperidine compounds disclosed herein have certain common featuresand process steps. For example, as shown, the processes for making thealkylated arylpiperazine and alkylated arylpiperidine compounds bothcomprise the step of alkylating the compound YH with a cyclic sulfate offormula (II) in the presence of a base to form a compound of formula(III) wherein Q is hydrogen, a metal, or an ammonium salt.

In preferred embodiments, R₁ and R₂ in formulas (II) and (III) areconnected to form a 5 to 8 carbon cyclic ring. Preferably, R₁ and R₂ areconnected to form a 5 or 6 carbon cyclic ring and, most preferably a 6carbon cyclic aliphatic ring.

In preferred embodiments, the compound YH is a cyclic imide or cyclicamide such that Y is NR₃R₄, where R₃ and/or R₄ are acyl, and wherein R₃and R₄ are connected to form a cyclic or bicyclic ring. Preferredcompounds that meet the requirements for YH include, for example:

TABLE 1 Representative Compounds of Formula YH Entry YH  1

  (3aR,4S,7R,7aS)-hexahydro- 1H-4,7-methanoisoindole- 1,3(2H)-dione  2

  1-(3-hydroxy-4- methoxyphenyl) ethan-1-one  3

  8-azaspiro[4.5]decane- 7,9-dione  4

  benzo[d]isothiazol- 3(2H)-one 1,1-dioxide  5

  (3aR,7aS)-hexahydro-1H- isoindole-1,3(2H)-dione  6

  7-hydroxyquinolin-2(1H)-one  7

  4,4- dimethylpiperidine- 2,6-dione  8

  N-(4-hydroxy-3- methoxyphenyl)acetamide  9

  4-methyl-1,2,4- triazine-3,5(2H,4H)- dione 10

  3-butyl-9,9-dimethyl-3,7- diazabicyclo[3.3.1]nonane- 2,4,6,8-tetraone11

  (3aR,4aR,6aS,7aS)- 3a,4,4a,6a,7,7a-hexahydro-1H-4,7-ethenocyclobuta[f]isoindole- 1,3(2H)-dione 12

  3-(hydroxymethyl)- 7-methoxy-4H- chromen-4-one 13

  quinazoline- 2,4(1H,3H)-dione 14

  2H-naphtho[1,8- cd]isothiazole 1,1-dioxide 15

  1,8,8-trimethyl-3- azabicyclo[3.2.1] octane-2,4-dione 16

  6-hydroxy-7-methoxy-3,4- dimethyl-2H-chromen-2-one

In a preferred embodiment of the present invention YH is:

In the reaction between compound YH and the cyclic sulfate of formula(II) in the present invention, compound YH is preferably present in thereaction mixture in an amount of from about 1.0 to 2.0 equivalents and,more preferably, from about 1.1 to 1.2 equivalents based on the amountof the cyclic sulfate of formula (II).

The alkylation reaction according to the present invention is preferablycarried out in a suitable solvent at a temperature of from about 20° C.to about 120° C. in the presence of a base.

Suitable solvents for this step include, but are not limited to,hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, esters,ethers, nitriles, ketones, and mixtures thereof. In preferredembodiments, the solvent is acetonitrile.

Suitable bases for this step include alkali metal carbonates such aspotassium carbonate, sodium carbonate, calcium carbonate, and magnesiumcarbonate; alkali metal bicarbonates such as sodium bicarbonate, andpotassium bicarbonate; preferably an alkali metal carbonate, inparticular, potassium carbonate; alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide, magnesium hydroxide, or calciumhydroxide; alkali metal phosphates such as sodium phosphate or potassiumphosphate; and organic amine bases such as triethylamine,diisopropylethylamine and pyridine. Ammonium salts of the above basesare also suitable. Solid inorganic bases may be used alone or as amixture of two or more kinds of bases, and may be an anhydrous form or ahydrate thereof. In preferred embodiments, the base employed for thisstep is potassium carbonate, K₂CO₃.

The amount of the base used herein is generally about 0.7 mole or more,preferably 1.0 mole or more, per one mole of the total amount ofcompound YH. The upper limit amount of the solid inorganic base usedherein is not limited but an excess amount of base can increase processcosts. Accordingly, a practical amount of solid inorganic base is 10mole or less, preferably 2.0 mole or less, per one mole of the totalamount of compound YH.

The progress of the alkylation reaction in the present invention can bemonitored by any means known to those skilled in the art such as, forexample, gas chromatography (GC) or high performance liquidchromatography (HPLC).

The compound of formula (III) may be isolated by any method known tothose skilled in the art. In preferred embodiments, however, thecompound of formula (III) is not isolated from the reaction mixture inwhich it was formed, but rather is telescoped. In this regard, thecompound of formula (III) may be readied for a hydrolysis step by theaddition of water, which generates a clean phase split with, forexample, acetonitrile due to the solubilized base such as, for example,potassium carbonate, without significant product loss. The organicsolvent layer is then preferably washed further with aqueous NaCl in aconventional extraction process to remove any residual carbonate priorto a hydrolysis reaction.

An unexpected benefit of employing a cyclic sulfate of formula (II) inthe process of the present invention is that it leads to theadvantageous selective monoalkylation of the cyclic sulfate without thepossibility of double alkylation. The anionic ring-opened sulfate (afterinitial alkylation) is not prone to further displacement bynucleophiles. Thus, after conversion of the alcohol to a suitableleaving group, simple displacement chemistry is employed to provide thefinal product. In other words, the process of the present inventionproduces alkylated arylpiperazine and alkylated arylpiperidine compoundswherein no bis-imide product is detected in the alkylation of the cyclicsulfate.

The process for making the alkylated arylpiperazine and arylpiperidinederivative compounds according to the present invention also comprisesthe step of hydrolyzing a compound of formula (III) to form an alcoholof formula (IV) as shown here.

In this reaction step, aqueous acid is added to a washed organic solventlayer containing the compound of formula (III) and the mixture isagitated at a temperature of from about 20° C. to about 100° C. Duringthis step, the sulfate ester moiety of the compound of formula (III) ishydrolyzed to an alcohol group (—OH). In some embodiments, an additionalsolvent such as, for example, toluene, may be added to the mixture priorto the aqueous acid.

The progress of the hydrolysis reaction in the present invention can bemonitored by any means known to those skilled in the art such as, forexample, high performance liquid chromatography (HPLC).

Preferably, once the reaction is complete, the organic phase is cooledand the organic phase is prepared for another step in the process of thepresent invention. This preparation typically involves washing severaltimes with water employing a conventional extraction process. Theorganic phase may also be distilled under vacuum followed by addition ofthe desired solvent for the next step of the process. An example of suchsolvent is toluene.

The process of the present invention for making alkylated arylpiperazineand alkylated arylpiperidine compounds also comprises a step ofconverting the compound of formula (IV) to an alkylating agent offormula (V) wherein LG is a leaving group.

In the compound of formula (V), preferably LG is selected from the groupconsisting of an aryl sulfonate, alkyl sulfonate, phosphate,phosphonate, proazaphosphatrane and a halogen. In preferred embodiments,LG is a mesylate.

The conversion of the hydroxyl group to one of the recited leavinggroups can be effected by any means known to one skilled in the art. Inpreferred embodiments where LG is a mesylate, for example, it was foundthat the conversion can occur quickly and effectively in a mixture oftoluene and a base such as, for example, triethylamine. In thisembodiment, about 1.2 equivalents of methanesulfonyl chloride relativeto the alcohol is added to the mixture to initiate the reaction. Othersuitable solvents for this step include, for example, hydrocarbons,halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers,nitriles, ketones, and mixtures thereof.

The progress of the conversion reaction in the present invention can bemonitored by any means known to those skilled in the art such as, forexample, HPLC. Such a reaction typically requires from about 0.5 hoursto about 12 hours for completion, depending on variables such as, forexample, temperature, equivalents of activating agent, and concentrationof the reactants. For example, the less solvent employed the faster thereaction is likely to proceed.

Once the reaction is complete, the mixture is preferably washed withwater. The aqueous layer can then be separated and removed following thewash. Preparation of the organic phase for the next step in the processof the present invention can be accomplished by vacuum distillationuntil the desired volume is reached.

The process of making alkylated arylpiperazine compounds according tothe present invention comprises a step of alkylating a piperazinecompound of formula (VI) with an alkylating agent of formula (V) toprovide the alkylated arylpiperazine of formula (I).

In the reaction between the compounds of formula (V) and (VI) in thepresent invention, the compound of formula (VI) is preferably present inthe reaction mixture in an amount of from 1.0 to 10.0 equivalents and,more preferably, from 1.1 to 1.2 equivalents based on the amount of thecompound of formula (V). Also present in the reaction is about 1.5equivalents of a base. Suitable bases for this step include alkali metalcarbonates such as potassium carbonate, sodium carbonate, calciumcarbonate, and magnesium carbonate; alkali metal bicarbonates such assodium bicarbonate, and potassium bicarbonate; preferably an alkalimetal carbonate, in particular, potassium carbonate; alkali metalhydroxides such as sodium hydroxide, potassium hydroxide, magnesiumhydroxide, or calcium hydroxide; alkali metal phosphates such as sodiumphosphate or potassium phosphate; and organic amine bases such astriethylamine, diisopropylethylamine and pyridine. Ammonium salts of theabove bases are also suitable. Solid inorganic bases may be used aloneor as a mixture of two or more kinds of bases, and may be an anhydrousform or a hydrate thereof. In preferred embodiments, the base employedfor this step is potassium carbonate, K₂CO₃. The amount of the base usedherein is generally about 0.7 mole or more, preferably 1.0 mole or more,per one mole of the total amount of compound of formula (VI). The upperlimit amount of the solid inorganic base used herein is not limited,but, in case that the amount is too much, the process cost increases.Accordingly, a practical amount of the base is 3 mole or less,preferably 2.0 mole or less, per one mole of the total amount ofcompound of formula (VI).

The progress of the reaction can be monitored by any means known tothose skilled in the art such as, for example, HPLC.

Once complete, the reaction mixture is preferably cooled followed byaddition of solvent. The aqueous layer is removed followed by additionalwashes of the organic phase with water. Once the aqueous layer isseparated, the organic layer is preferably distilled under vacuum and anantisolvent is added. Suitable antisolvents for this step include, butare not limited to, hydrocarbons, halogenated hydrocarbons, aromatichydrocarbons, esters, ethers, nitriles, ketones, and mixtures thereof.To effect crystallization of the arylpiperazine of formula (I), themixture is preferably successively heated and cooled in the mixture ofsolvent and antisolvent.

The process of making alkylated arylpiperidine compounds according tothe present invention comprises a step of alkylating an arylpiperidinecompound of formula (VIII) with an alkylating agent of formula (V) toprovide the alkylated arylpiperidine of formula (VII).

The reaction conditions and product separation are about the same asthose described above regarding the alkylated arylpiperazine compounds.

As will be understood by those of ordinary skill in the art, theprocesses described above and herein can be employed to produce avariety of compounds. For example, as shown in Table 2 below, thefollowing compounds can be made by the process described herein formaking the alkylated arylpiperazine compound of formula (I).

TABLE 2 Compounds of Formula (I) Compound Name Structure R1 R2 n YH ArLurasidone

—((CH₂)₄)— NA 2

  (3aR,4S,7R,7aS)-hexahydro-1H- 4,7-methanoisoindole-1,3(2H)- dione

  3-benzo[d]isothiazolyl Tiospirone

H H 2

  8-azaspiro[4.5]decane-7,9-dione

  3-benzo[d]isothiazolyl Revospirone

H H 1

  benzo[d]isothiazol- 3(2H)-one 1,1-dioxide

  2-pyrimidinyl Aripiprazole Lauroxil

H H 2

  7-hydroxyquinolin-2(1H)-one

  2,3-dichlorophenyl Buspirone

H H 2

  8-azaspiro[4.5]decane- 7,9-dione

  2-pyrimidinyl Gepirone

H H 2

  4,4-dimethylpiperidine- 2,6-dione

  2-pyrimidinyl Ipsapirone

H H 2

  benzo[d]isothiazol- 3(2H)-one 1,1-dioxide

  2-pyrimidinyl Eptapirone

H H 2

  4-methyl-1,2,4- triazine-3,5-(2H,4H)- dione

  2-pyrimidinyl Umespirone

H H 2

  3-butyl-9,9-dimethyl-3,7- diazabicyclo[3.3.1]nonane- 2,4,6,8-tetraone

  2-methoxyphenyl Zalospirone

H H 2

  (3aR,4aR,6aS,7aS)- 3a,4,4a,6a,7,7a-hexahydro-1H-4,7-ethenocyclobuta[f]isoindole- 1,3(2H)-dione

  2-pyrimidinyl Pelanserin

H H 1

  quinazoline-2,4(1H,3H)-dione

  phenyl Fananserin

H H 1

  2H-naphtho[1,8- cd]-isothiazole 1,1-dioxide

  4-fluorophenyl Piricapiron

H H 2

  1,8,8-trimethyl-3- azabicyclo[3.2.1]octane-2,4- dione

  2-pyridyl OPC-4392

H H 1

  7-hydroxyquinolin-2(1H)-one

  2,3-dimethylphenyl Mafoprazine

H H 1

  N-(4-hydroxy-3- methoxyphenyl)acetamide

  2-fluorophenyl Enasculin

H H 1

  6-hydroxy-7-methoxy-3,4- dimethyl-2H-chromen-2-one

  2-methoxyphenyl

TABLE 3 Compounds of Formula (VII) Compound Name Structure R1 R2 n YH ArIloperidone

H H 1

  1-(3-hydroxy-4- methoxyphenyl)ethan-1-one

  6-fluoro-3- benzo[d]isoxazolyl Abaperidone

H H 1

  3-(hydroxymethyl)- 7-methoxy-4H- chromen-4-one

  6-fluoro-3- benzo[d]isoxazolyl

In the process of making the alkylated arylpiperazine and alkylatedarylpiperidine compounds disclosed herein, numerous intermediatecompounds are produced.

The following examples illustrate various aspects of the presentinvention.

EXAMPLES Example 1 Telescoped Preparation of(5aR,9aR)-octahydrobenzo[e][1.3.2]dioxathiepine 3,3-dioxide

[(1R,2R)-cyclohexane-1,2-diyl]dimethanol (mol. wt. 144.21) is added toacetonitrile providing a reaction mixture in the form of a suspension.The mixture is stirred and cooled to 0-5° C. Thionyl chloride is addedto the mixture at a temperature of 0-10° C. which results in a clearsolution. The solution is stirred at 0-5° C. and assayed periodically toconfirm completion of the reaction.

In a separate vessel, an aqueous solution of potassium bicarbonate (2.5eq) is added prepared and then cooled to 0-5° C. The completed reactionsolution above is then quenched into the aqueous potassium bicarbonatesolution. The batch is then warmed to 20-25° C. and the upperacetonitrile layer is separated and collected. The aqueous layer isextracted with acetonitrile and the organic layers are combinedresulting in a solution of(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide (mol. wt.190.26).

In a separate vessel, 50% ruthenium oxide hydrate (0.1 wt. %) and sodiumperiodate (1.1 eq.) are slurried in water (and EtOAc at 20-25° C. The(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide solution aboveis then added to the sodium periodate/ruthenium oxide slurry whilemaintaining the temperature at ≦30° C. After the reaction is complete,the batch is then filtered, after which the filter cake is washed withEtOAc. The upper organic layer is collected and washed with 20% aqueoussodium chloride. The organic layer is distilled to a minimum volumeafter which isopropanol is added to the distillate. The resulting slurryis heated to 40-45° C. after which it is cooled to 0-5° C., and thenfiltered. The solids are washed with isopropanol and dried in a vacuumoven resulting in (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine3,3-dioxide (mol. wt. 206.26).

Example 2 Telescoped Preparation of Lurasidone Free Base

Acetonitrile is added to a mixture of(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3,3-dioxide (mol. wt.206.26, 1 eq.),(3aR,4s,7R,7aS-hexahydro-1H-7,4-methanoisoindole-1,3(2H)-dione (mol. wt.165.19, 1.2 eq.) and potassium carbonate (2 eq.) and the mixture isheated to about 75° C.

After the reaction is complete, the mixture is cooled to 20-25° C. andwater is added to the mixture. A lower, aqueous phase is then removedand an upper, organic phase is washed with aqueous sodium chloride.

The aqueous phases are combined and extracted with acetonitrile. Theorganic phases are combined to form a solution of potassium ((1R,2R)-2(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methyl sulfate (mol. wt. 409.54) in acetonitrile which isthen distilled to approximately 5 volumes. Toluene is added to the batchand, separately a solution of sulfuric acid (0.5 eq.) and water (0.6volumes) is prepared. The sulfuric acid solution is added to the batch.This mixture is then heated to approximately 75° C. and the reaction ismonitored by HPLC.

Once the reaction is complete, it is cooled to approximately 45° C. andwashed twice with water (4 volumes). The aqueous layer is then removedand the organic layer is washed with 5% aqueous KHCO₃ (4 volumes)followed by two additional water washes (4 volumes). The organicsolution comprising(3aR,4S,7R,7aS)-2-(((1R,2R)-2-(Hydroxymethyl)cyclohexyl)methyl)hexahydro-1H-4,7methanoisoindole-1,3(2H)-dione(mol. wt. 291.39) is distilled under vacuum to approximately 4 volumesand toluene is added to the batch. This solution is distilled toapproximately 4 volumes and toluene is added. This batch is cooled toabout 0-5° C., and triethylamine (1.5 eq.) is added after whichmethanesulfonyl chloride (1.2 eq.) is added. The progress of thisreaction is monitored by HPLC.

Once the reaction is complete, water (3 volumes) is added. The aqueouslayer is removed and the organic layer is washed with water (2×3volumes).

The toluene solution of((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methylmethanesulfonate is distilled to about 4 volumes under vacuum, and thissolution is added to a mixture of 3-(piperazin-1-yl)benzold]isothiazole(1.1 eq.) and KHCO₃ (1.5 eq.). Water (1.8 volumes) is added and themixture is heated to approximately 90° C. The progress of the reactionis monitored by HPLC.

Once the reaction is complete, the batch is cooled to 45±5° C. andtoluene (4.5 volumes), water (3.25 volumes), and IPA (1.75 volumes) areadded. The aqueous layer is removed and the organic layer is washed withwater (2×2.5 volumes) at 40±5° C. The organic layer is distilled underreduced pressure to 3.5 volumes at 50-60° C., then isopropanol (8volumes) is added. The batch is distilled to 3.5 volumes, then IPA (2.5volumes) is added. The slurry is heated to 80±5° C. for 1-2 hours, thencooled to 0-5° C. and filtered. The solids are washed with IPA and driedto isolate(3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzol[d]isothiazol-3-yl)piperazin-1-yl)methylcyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (lurasidone free base,mol. wt. 492.68).

Example 3 Crystallization of Lurasidone Free Base

The crude lurasidone free base of Example 2 is slurried in ethyl acetate(10 volumes) and heated until a clear solution is obtained. The solutionis cooled to 50-55° C. and filtered to remove any particulates in thesolution. The solution is further distilled to approximately 4-5 volumesand then cooled to approximately 0-5° C. The resulting solid precipitateis filtered, rinsed with ethyl acetate and then dried under vacuum toprovide crystalline lurasidone free base.

Example 4 Preparation of Lurasidone Hydrochloride

The lurasidone free base of Example 3 is slurried in isopropanol (1 eq.base to 15 volumes of isopropanol). The slurry is then heated until aclear solution results. The solution is filtered to remove anyparticulates in the solution. A pre-filtered solution of 10% aqueous HClis then added, and the batch is slowly cooled to approximately 45-70° C.until crystals begin to precipitate. The batch is held at this point forseveral hours, then further cooled to approximately 0° C. The resultingsolid precipitate is filtered and then washed with isopropanol (3×2volumes). The precipitate is dried to provide lurasidone hydrochloride.

Example 5 Telescoped Preparation of (3-(5-acetyl-2-methoxyphenoxy)propylmethanesulfonate towards Iloperidone

A mixture of 1,3,2-dioxathiane 2,2-dioxide (22.4 g, 160 mmol, 1 eq.),1-(3-hydroxy-4-methoxyphenyl)ethan-1-one (26.9 g, 160 mmol, 1 eq.) andpotassium carbonate (44.8 g, 320 mmol, 2 eq.) in acetonitrile (220 mL)is heated at about reflux temperature. The reaction is monitored byHPLC. Upon completion, the batch is cooled to about 20-25° C. Thereaction mixture is filtered through a Celite pad and the pad is washedwith acetonitrile (180 mL) to give a solution of potassium3-(5-acetyl-2-methoxyphenoxy)propyl sulfate in acetonitrile, which isused in the next step.

A solution of H₂SO₄ (10 mL H₂SO₄ in 90 mL water) is added slowly to theabove acetonitrile solution. The batch is then heated to about reflux;the reaction is monitored by HPLC. Upon completion, the reaction mixtureis cooled to about 20-25° C., and the resulting phases separated. Theorganic phase is washed with brine (100 mL×2) and divided into 2portions (80 mL and 320 mL).

The 80 mL portion from the above reaction is worked up to provide areference marker of 1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-oneas follows. The solvent is removed under reduced pressure to give thecrude product, which is purified by column chromatography on silica gel(10× silica gel relative to crude product, petroleum ether:ethyl acetate[2:1] to petroleum ether:ethyl acetate [1:1]) to give1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-one in 99% purity (2.3g, white solid).

A large portion of the acetonitrile solution of potassium3-(5-acetyl-2-methoxyphenoxy)propyl sulfate (320 mL) is progressedforward as follows. Approximately 80% of the solvent is removed, andthen ethyl acetate (200 mL) is added. About 80% of the solvent isremoved again to give a concentrated solution of1-(3-(3-hydroxypropoxy)-4-methoxyphenyl)ethan-1-one in ethyl acetate forthe next step.

Triethylamine (75 g) and ethyl acetate (200 mL) are added to the abovesolution, then a solution of Ms₂O (40 g) in ethyl acetate (200 mL) isadded dropwise at less than 15° C. The mixture is stirred at about 10°C. overnight. The reaction is monitored by HPLC. Aqueous sodiumhydroxide (15%, 250 mL) is added when the reaction is completed, and themixture is stirred at about 20-25° C. for 15 min. The separated organiclayer is then washed with 2 M HCl (200 mL) and brine (200 mL). Thesolvent is removed under reduced pressure to give the crude product(3-(5-acetyl-2-methoxyphenoxy)propyl methanesulfonate as an off-whitesolid (15 g, 90% AUC by HPLC).

Example 6 Preparation of Iloperidone Free Base

A mixture of 3-(5-acetyl-2-methoxyphenoxy)propyl methanesulfonate (3 g,10 mmol, 1 equiv), 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.42 g,11 mmol, 1.1 equiv), KHCO₃ (1.5 g, 15 mmol, 1.5 equiv), H₂O (6 g) andtoluene (15 mL) is heated at reflux temperature for 12-16 h. Once thereaction is complete, the batch is cooled to about 20-25° C., and thentoluene (15 mL), IPA (10 mL) and water (10 mL) are added. The biphasicsolution is stirred for about 15 min at about 20-25° C. The organiclayer is separated and washed with water (2×10 mL). The batch isconcentrated to about 3-4 volumes under vacuum at <50° C. to precipitatean off-white solid. Isopropanol (20 mL) is added, the batch isconcentrated to 3-4 volumes under vacuum at <50° C. Isopropanol (20 mL)is added again, and the batch is concentrated to 3-4 volumes undervacuum at <50° C. Isopropanol (10 mL) is added once again and the batchis heated at reflux temperature for 1 h, and then the mixture is cooledto 5-8° C. over 4 h. The mixture is filtered; the cake is washed withisopropanol (2×5 mL) and dried to give Iloperidone free base (3.1 g, 74%yield, 98% AUC by HPLC).

Example 7 Preparation of Potassium4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfate towardsIpsapirone

A mixture of benzo[d]isothiazol-3(2H)-one 1,1-dioxide (16.0 g, 87.3mmol, 1.0 eq.), 1,3,2-dioxathiepane 2,2-dioxide (15.3 g, 100.5 mmol, 1.2eq.), K₂CO₃ (24.1 g, 174.6 mmol, 2.0 eq.) and ACN (240 mL) is heated atreflux temperature for 20 h. After the reaction is complete, the mixtureis filtered and concentrated under vacuum to give an oily product. Tothe residue is added ACN (200 mL), and a solid is precipitatedimmediately. The mixture is stirred for 1 h at 20-25° C., then filtered.Potassium 4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfateis collected as a white solid (11.4 g, 35% yield, 98.5% AUC by HPLC);LC-MS, M⁺: 335.6 (sulfonic acid).

Example 8 Preparation of 2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide towards Ipsapirone

A solution of H₂SO₄ (0.8 g, 8.2 mmol, 0.5 eq.) in H₂O (2 mL) is added toa mixture of potassium4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl sulfate (6.1 g,16.3 mmol, 1.0 eq.) in ACN (90 mL) and H₂O (5 mL) dropwise. Theresulting mixture is heated at 75-80° C. until the reaction is deemedcomplete by HPLC analysis. The mixture is filtered, and filtrate isconcentrated to approximately to 10 mL. To the residue, dichloromethaneand DI water are added. The layers are separated and the organic layeris washed with saturated NaHCO₃ solution, dried over sodium sulfate andthen concentrated to give the crude product in 94% purity by HPLC. Thecrude material is further purified by silica gel column chromatography(petroleum ether:ethyl acetate 4:1 to 3:1) to provide2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide as a lightyellow oil in (2.3 g, 55% yield, 99% AUC by HPLC); LC-MS, M*: 255.8.

Example 9 Preparation of4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butyl methanesulfonatetowards Ipsapirone

To a mixture of 2-(4-hydroxybutyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide (17.2 g, 67.4 mmol, 1.0 eq.) in ethyl acetate (172 mL, 10vol), is added triethylamine (13.6 g, 134.7 mmol, 2.0 eq.) at <5° C.,followed by dropwise addition of Ms₂O (12.9 g, 74.1 mmol, 1.1 eq.) inethyl acetate (20 mL) at 5-15° C. The mixture is stirred at 20-25° C.for 20 h and the reaction is deemed complete by HPLC. The mixture iswashed with H₂O twice, then dried over Na₂SO₄. The solvent is removedunder reduced pressure to obtain crude material. The crude product ispurified by column chromatography on silica gel (30× silica gel,petroleum ether:ethyl acetate [10:1] to petroleum ether ethyl acetate[4:1]) which gives 4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butylmethanesulfonate as a white solid (8.5 g, 38% yield, 96% AUC by HPLC);LC-MS, M⁺: 355.6.

Example 10 Preparation of Ipsapirone Free Base

A suspension of (1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butylmethanesulfonate (4.6 g, 13.8 mmol, 1.0 eq),2-(piperazin-1-yl)pyrimidine (2.9 g, 17.9 mmol, 1.3 eq.), KHCO₃ (2.1 g,20.7 mmol, 1.5 eq.) and toluene (46 mL) is heated at 95-100° C. for 22h. Deionized water (35 mL) is added, and the organic phase is separated.The aqueous phase is extracted with ethyl acetate (2×30 mL). The organicphases are combined and dried over Na₂SO₄. The solvent is removed underreduced pressure to give the crude product, which is purified by columnchromatography on silica gel by elution with 17-33% EtOAc/petroleumether to offer ipsapirone free base as an off-white solid (2 g, 27%yield, 96% AUC by HPLC).

The foregoing examples and description of the preferred embodimentsshould be taken as illustrating, rather than as limiting the presentinvention as defined by the claims. As will be readily appreciated,numerous variations and combinations of the features set forth above canbe utilized without departing from the present invention as set forth inthe claims. Such variations are not regarded as a departure from thespirit and scope of the invention, and all such variations are intendedto be included within the scope of the following claims.

What is claimed is:
 1. A process for preparing an alkylatedarylpiperazine compound of formula (I):

wherein, R₁ and R₂ are individually selected from hydrogen,unsubstituted alkyl, and substituted alkyl, or R₁ and R₂ are connectedto form a 5 to 8 carbon cyclic ring; n is 0, 1, or 2; Y is NR₃R₄, OR₅,or SR₅, where R₃ and R₄ are individually selected from acyl or sulfonyl,wherein R₃ and R₄ may be connected to form a substituted orunsubstituted cyclic or bicyclic ring, and wherein R₅ is aryl orheteroaryl, or heterocyclic; and Ar is an aryl or heteroaryl group; saidprocess comprising the steps of: (i) alkylating YH with a cyclic sulfateof formula (II) in the presence of a base to form a compound of formula(III), wherein Q is hydrogen, a metal, or an ammonium salt;

(ii) hydrolysing the compound of formula (III) to form an alcohol offormula (IV);

(iii) converting the compound of formula (IV) to form an alkylatingagent of formula (V) wherein LG is a leaving group; and

(iv) alkylating a piperazine compound of formula (VI) with thealkylating agent of formula (V) to provide the alkylated arylpiperazineof formula (I)


2. The process of claim 1, wherein R₁ and R₂ individually form part of aC₅, C₆, or C₇ cyclic ring.
 3. The process of claim 1, wherein R₃ and R₄individually form part of a C₅, C₆, or C₇ cyclic ring.
 4. The process ofclaim 1, wherein the leaving group LG is selected from the groupconsisting of an aryl sulfonate, alkyl sulfonate, phosphate,phosphonate, proazaphosphatrane, and a halogen.
 5. The process of claim1, wherein the compound of formula (I) is selected from the groupconsisting of lurasidone, tiospirone, revospirone, perospirone,brexipirazole, aripiprazole, aripiprazole lauroxil, buspirone, gepirone,ipsapirone, eptapirone, umespirone, tandospirone, zalospirone,pelanserin, fananserin, piricapiron, DU-125530, OPC-4392, mafoprazine,and enasculin.
 6. A process for preparing an alkylated arylpiperidinecompound of formula (VII):

wherein, R₁ and R₂ are individually selected from hydrogen,unsubstituted alkyl, and substituted alkyl, or R₁ and R₂ are connectedto form a 5 to 8 carbon cyclic ring; n=0, 1, or 2; Y is NR₃R₄, OR₅, orSR₅, where R₃ and R₄ are individually selected from acyl or sulfonyl,wherein R₃ and R₄ may be connected to form a substituted orunsubstituted cyclic or bicyclic ring, and wherein R₅ is aryl orheteroaryl, or heterocyclic; and Ar is an aryl or heteroaryl group, saidmethod comprising: (i) alkylating YH with a cyclic sulfate of formula(II) in the presence of a base to form a compound of formula (III),wherein Q is hydrogen, a metal, or an ammonium salt;

(ii) hydrolysing the compound of formula (III) to form an alcohol offormula (IV);

(iii) converting the compound of formula (IV) to form an alkylatingagent of formula (V), wherein LG is a leaving group; and

(iv) alkylation of a piperidine of formula (VIII) with the alkylatingagent of formula (V) to provide an alkylated arylpiperadine compound offormula (VII)


7. The process of claim 6, wherein R₁ and R₂ individually form part of aC₅, C₆, or C₇ cyclic group.
 8. The process of claim 6, wherein R₃ and R₄individually form part of a C₅, C₆, or C₇ cyclic group.
 9. The processof claim 6, wherein the leaving group LG is selected from the groupconsisting of an aryl sulfonate, an alkyl sulfonate, phosphate,phosphonate, proazaphosphatrane, and a halogen.
 10. The process of claim6, wherein the alkylated arylpiperadine compound of formula (VII) isiloperidone or abaperidone.
 11. A compound of formula (III):

wherein, R₁ and R₂ are individually selected from hydrogen,unsubstituted alkyl, and substituted alkyl, or R₁ and R₂ are connectedto form a 5 to 8 carbon cyclic ring; n=0, 1, or 2; Y is NR₃R₄, OR₅, orSR₅, where R₃ and R₄ are individually selected from acyl or sulfonyl,wherein R₃ and R₄ may be connected to form a substituted orunsubstituted cyclic or bicyclic ring, and wherein R₅ is aryl orheteroaryl, or heterocyclic; and Q is hydrogen, a metal, or an ammoniumsalt.
 12. A compound having the structure:

wherein Q is hydrogen, a metal, or an ammonium salt.
 13. A compoundhaving the structure:

wherein Q is hydrogen, a metal, an ammonium salt, a methyl group, anaryl group, or a substituted aryl group, and wherein n=2 or
 3. 14. Aprocess for preparing lurasidone comprising the steps of: (i) alkylating(3aR,4S,7R,7aS)-hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione byreacting it with(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine-3,3-dioxide in thepresence of K₂CO₃ to form potassium((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methylsulfate; (ii) hydrolyzing potassium((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methylsulfate to form(3aR,4S,7R,7aS)-2-(((1R,2R)-2-(hydroxymethyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; (iii) reacting(3aR,4S,7R,7aS)-2-(((1R,2R)-2-(hydroxymethyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione with methanesulfonylchloride to form((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methylmethanesulfonate; and (iv) reacting3-(piperazin-1-yl)benzo[d]isothiazole with((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methylmethanesulfonate to form(3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione(Lurasidone).